The events on and following September 11, 2001 have revealed our nation's vulnerability to terrorist attacks. Although much talked about during the past decade, the threat of a bioterrorist attack against the United States was not realized until the intentional distribution of weapons grade Bacillus anthracis via the U.S. postal service. These attacks combined with questions concerning the safety of the current vaccine against B. anthracis warrant the rapid development of a new B. anthracis vaccine that is both safe and effective. Using the most recent technological advances in vaccine research, a novel vaccine will be developed that relies upon simultaneous expression of mutant forms of B. anthracis Protective Antigen (PA) and Lethal Factor (LF) in each of two different types of viral vectors. The first vector will be based on vaccinia virus, the virus that was used to eradicate smallpox. The MVA strain of vaccinia virus will be used to construct the vector inasmuch as this strain is attenuated and has been proven to be safe in humans. The second vector will be based on a replication-competent adenovirus vector, allowing high-level expression of the target antigens. A number of vaccine and cancer gene therapy vectors have been developed using replication-competent adenoviruses, emphasizing their safety in humans. The vaccinia- and adenovirus-based vectors will be evaluated individually and in combination for their ability to induce humoral and cell-mediated immune responses in a mouse model. It is anticipated that a prime and boost protocol in which the mice are first immunized with one vector and then immunity is boosted using the second vector will be most effective at generating a robust immune response to the PA and LF antigens. It is anticipated that in a Phase II application, the ability of these two vectors to protect from B. anthracis challenge will be assessed.